Abstract Heart disease remains the leading cause of death in the US, accounting for nearly 40% of all deaths annually. A high cholesterol level is a well-known risk factor for heart disease. Although blood cholesterol (low density lipoprotein, LDL-C) can be lowered using a number of marketed drugs, only 38% of patients taking these drugs are achieving the desired goals. Furthermore, patients with homozygous familial hypercholesterolemia, who have markedly elevated cholesterol levels, respond poorly to current drug therapies, and are at very high risk of premature cardiovascular disease. These and other patients will benefit from an aggressive treatment of hypercholesterolemia. A newly discovered protein- proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in cholesterol homeostasis by the expression of low-density lipoprotein receptor (LDLR) on the cell membrane. In fact, gain- and loss-of-function PCSK9 variations in human populations are associated with hyper- or hypo cholesterolemia respectively. Therefore, PCSK9 inhibition has emerged as a promising option to treat hypercholesterolemia. Indeed, several strategies have been applied in the development of PCSK9 inhibitors including monoclonal antibodies (mAbs), and recently FDA has approved two anti-PCSK9 mAbs. However, no orally administrable small molecules are approved. Thus, our approach is to develop a small molecule PCSK9 inhibitor. Using our novel and disruptive HPC-based platform, we have characterized PCSK9 structure at the atomic level and generated numerous trajectories via molecule dynamic simulations. We have validated several ?hits? molecules in experimental assays. We plan to develop the hits and generate lead molecules of diverse scaffolds using in vivo cellular assays and transgenic efficacy animal.